Mutations

PSEN2 S130L

Overview

Pathogenicity: Alzheimer's Disease : Unclear Pathogenicity
Clinical Phenotype: Alzheimer's Disease, None, Parkinson's Disease Dementia
Reference Assembly: GRCh37 (105)
Position: Chr1:227073271 C>T
dbSNP ID: rs63750197
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: TCG to TTG
Reference Isoform: PSEN2 isoform 1 (448 aa)
Genomic Region: Exon 5

Findings

The S130L variant has been detected in several Alzheimer's disease patients with a family history of disease, most having early-onset presentation. However, evidence for segregation with disease is lacking. 

The S130L variant was first reported in a kindred from northern Italy (FL056) (Sorbi et al., 2002; Tedde et al., 2003). The proband experienced symptom onset, chiefly memory loss, at age 65. The proband had a family history of dementia, with an affected mother, uncle, and grandfather. Onset age was 65 for the mother and uncle, and unknown for the grandfather. In this family the clinical presentation was characterized by a long disease duration, with many years of mild cognitive impairment before the development of bona fide dementia. Segregation with disease could not be determined.

This variant was also identified in a patient with apparent late-onset, sporadic AD (Tomaino et al., 2007). This patient had disease onset at age 81 with progressive memory impairment and spatial disorientation, as well as mood and personality changes. He rapidly developed language deficits, agitation, delusions, hallucinations, agnosia, aphasia, and mild bradykinesia. Two of the proband's siblings were reported to have Parkinson's disease, but were cognitively healthy. Segregation with disease could not be determined.

The S130L variant was detected in a Turkish individual who developed late-onset AD (Lohmann et al., 2012). His symptoms started at age 77, with depression, progressive memory impairment, and episodes of spatial disorientation. He also developed mild bradykinesia. His mother and maternal uncle were also affected by memory problems. Segregation with disease could not be determined.

The S130L variant was also one of several rare variants detected by exome sequencing in a British cohort composed of 47 unrelated, early onset AD cases and 179 elderly controls free of AD pathology. The variant was detected in one AD case and one control case. The AD patient developed cognitive symptoms at age 61 and died at age 65 with autopsy-confirmed AD. The precise age of the elderly control case was not reported (Sassi et al., 2014).

This variant was also reported in an individual with idiopathic Parkinson’s disease with dementia (Schulte et al., 2015). This individual first developed symptoms at age 73, beginning with bradykinesia. Later symptoms included resting tremor, rigor, postural instability, and dementia.

In a recent study using whole-exome sequencing, this variant was identified in three of 424 French people with early onset AD (Nicolas et al., 2015). Associated clinical data were limited for these individuals. Two of the S130L carriers had apparently sporadic AD with onset at ages 51 and 62, respectively. The third individual had a family history of dementia; however, segregation with disease could not be assessed. This individual was 65 at onset and had an APOE genotype of E3/E3.

In addition to the germ-line mutations described above, this variant was also one of three mosaic mutations detected in AD-related genes in the brain by deep sequencing (Sala Frigerio et al., 2015). Of the 130 entorhinal cortex samples analyzed, the S130L variant was detected in one control sample at an allelic frequency of about 1 percent. This individual died at age 90 with mild AD pathology (modified Braak stage II). The significance of a low frequency mosaic mutation in the brain is currently unclear.

The S130L variant is also associated with dilated cardiomyopathy in at least two families, although penetrance is incomplete (Li et al., 2006).

Neuropathology

At least one affected mutation carrier had neuropathology consistent with AD at autopsy (Sassi et al., 2014). In addition, Aβ43/Aβ40 and Aβ42/Aβ40 ratios were decreased in the CSF of a Belgian carrier with an APOE3/E3 genotype (Perrone et al., 2020). Also, in this same individual, Aβ40, Aβ42, Aβ43, sAPPα, sAPPβ levels were reduced. Tau and phospho-tau levels were comparable to those of controls.

Biological Effect

Despite the reduced CSF Aβ43/Aβ40 and Aβ42/Aβ40 ratios described above, in vitro studies suggest a lack of an effect of S130L on APP processing. When transfected into fibroblasts lacking endogenous PSEN1 and PSEN2, the S130L variant did not affect levels of the proteolytic products PSEN2-CTF and PSEN2-NTF compared with wild-type PSEN2, indicating that the substitution does not alter steady-state endoproteolytic activity. In addition, when co-transfected with APP carrying the Swedish mutation, the S130L mutation did not affect Aβ42 levels or the Aβ42/Aβ40 ratio (Walker et al., 2005). Calcium signaling was altered in cultured skin fibroblasts from mutation carriers. Specifically, the resting intracellular calcium concentration was elevated (Li et al., 2006).

In silico analyses have predicted the S130L variant to be "possibly damaging" (Sassi et al., 2014; Lohmann et al., 2012, Hsu et al., 2020) or "damaging" (Hsu et al., 2020). This residue is not conserved between PSEN2 and PSEN1.

Lohmann and colleagues classified S130L as "probably pathogenic" based on the algorithm proposed by Guerreiro et al. (Lohmann et al., 2012; Guerreiro et al., 2010) and Perrone et al. described it as "likely pathogenic" citing Lohmann's classification and the reduced CSF Aβ43/Aβ40 and Aβ42/Aβ40 ratios (Perrone et al., 2020). In contrast, Hsu and colleagues predicted the variant is either “not pathogenic” or a  “risk factor” (Hsu et al., 2020).

Last Updated: 27 Oct 2020

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

Paper Citations

  1. . Novel presenilin 1 and presenilin 2 mutations in early-onset Alzheimer's disease families. Neurobiol Aging. 2002 Jul-Aug;23(1S):312.
  2. . Identification of new presenilin gene mutations in early-onset familial Alzheimer disease. Arch Neurol. 2003 Nov;60(11):1541-4. PubMed.
  3. . Presenilin 2 Ser130Leu mutation in a case of late-onset "sporadic" Alzheimer's disease. J Neurol. 2007 Mar;254(3):391-3. PubMed.
  4. . Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish dementia patients. Neurobiol Aging. 2012 Aug;33(8):1850.e17-27. PubMed.
  5. . Exome sequencing identifies 2 novel presenilin 1 mutations (p.L166V and p.S230R) in British early-onset Alzheimer's disease. Neurobiol Aging. 2014 Oct;35(10):2422.e13-6. Epub 2014 May 2 PubMed.
  6. . Rare variants in β-Amyloid precursor protein (APP) and Parkinson's disease. Eur J Hum Genet. 2015 Jan 21; PubMed.
  7. . Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons. Eur J Hum Genet. 2015 Aug 5; PubMed.
  8. . Mutations of presenilin genes in dilated cardiomyopathy and heart failure. Am J Hum Genet. 2006 Dec;79(6):1030-9. Epub 2006 Oct 24 PubMed.
  9. . Amyloid-β1-43 cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations. Alzheimers Res Ther. 2020 Sep 11;12(1):108. PubMed.
  10. . Presenilin 2 familial Alzheimer's disease mutations result in partial loss of function and dramatic changes in Abeta 42/40 ratios. J Neurochem. 2005 Jan;92(2):294-301. PubMed.
  11. . Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.
  12. . Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.

Other Citations

  1. Sala Frigerio et al., 2015

Further Reading

Protein Diagram

Primary Papers

  1. . Novel presenilin 1 and presenilin 2 mutations in early-onset Alzheimer's disease families. Neurobiol Aging. 2002 Jul-Aug;23(1S):312.
  2. . Identification of new presenilin gene mutations in early-onset familial Alzheimer disease. Arch Neurol. 2003 Nov;60(11):1541-4. PubMed.

Alzpedia

Disclaimer: Alzforum does not provide medical advice. The Content is for informational, educational, research and reference purposes only and is not intended to substitute for professional medical advice, diagnosis or treatment. Always seek advice from a qualified physician or health care professional about any medical concern, and do not disregard professional medical advice because of anything you may read on Alzforum.